Are You Confident of the Diagnosis?

What you should be alert for in the history

Steroid sulfatase (STS, also known as arylsulfatase C) deficiency results in the clinical disorder X-linked ichthyosis (XLI), a disorder of keratinization characterized by dark-appearing polygonal scale. The scaling is predominantly located on the body’s extensor surfaces in older affected children and adults, often sparing the face (Figure 1, Figure 2).

Figure 1.

Plate-like thick brown scale of XLI (Courtesy of Bryan Anderson, MD)

Figure 2.

A family history may be notable for the presence of affected males linked by unaffected females. Most commonly, XLI is caused by a full-length deletion of the STS gene, located on the short arm of the X chromosome (Figure 3). XLI is relatively common, with a prevalence in males estimated as 1 in 1500 to 1 in 6000.

Figure 3.

If the deletion extends beyond the STS gene to include neighboring genes, a more complex phenotype ensues depending upon the specific boundaries of the deletion. XLI itself comprises ichthyosis of variable severity, corneal opacities, and less commonly, cryptorchidism and rare germ cell tumors in affected males. Heterozygous females have normal skin but may have asymptomatic corneal opacities and pregnancy-related concerns.

Characteristic findings on physical examination

Affected males may have scaling in the neonatal period, but more typically develop scaling over the first few weeks or months of life. The appearance of the scales is variable: commonly, the scale shape is polygonal and the color darkens over time to a “dirty”-appearing grey-brown, but there is great variability in the appearance of the scale (Figure 1, Figure 2).

Scaling is located mostly on the extensor surfaces of the body and the sides of the trunk, sparing the face, although the scalp and neck are often affected in infancy. The ichthyosis is particularly common over the shins. Milder cases may mimic ichthyosis vulgaris.

Corneal opacities are asymptomatic. They appear as very fine, punctate opacities detectable via slit lamp examination and are usually located in the posterior corneal stroma or Descemet membrane. They may be detected in the teenage years or early adulthood in 10% to 50% of affected males and in 25% of carrier females. They are part of “category 4” in the recent classification of corneal dystrophies (The International Committee for Classification of Corneal Dystrophies-IC3D).

About 20% of affected males also have cryptorchidism. In addition to, and unrelated to any preceding history of cryptorchidism, there is a small risk of testicular germ cell tumors. These gonadal problems, also not related to co-deletion of contiguous genes, include the Kallmann syndrome gene locus.

In males with larger contiguous gene deletions that include STS, the phenotype depends on the extent of the deletion. Heterozygotes do not have visible clinical findings except for asymptomatic corneal opacities in 25%. However, STS deficiency may be associated with delayed or protracted labor for mothers of affected males due to placental STS deficiency.

Pregnant mothers often have markedly diminished levels of estriol, now readily detected with widely used maternal serum screening. This can erroneously lead to concern about other more serious genetic and chromosomal conditions such as Down syndrome, Smith-Lemli-Opitz syndrome, and multiple sulfatase deficiency. Routine prenatal screening is thus likely to increase the overall number of XLI cases that are diagnosed.

Expected results of diagnostic studies

The diagnosis may be strongly suspected when there are other affected males in the family in a pattern suggestive of X-linked inheritance, with affected males linked through unaffected carrier females. In pregnancy, very low maternal serum estriol levels with normal levels of other serum screening markers may suggest the diagnosis, particularly when coupled with a suggestive family history.

Skin biopsy is typically non-specfic and, therefore, not helpful in diagnosis. Findings include hyperkeratosis with a variably increased granular layer. There may be mild perivascular inflammation in the dermis with edema.

Although enzymatic assay may be performed in WBCs, keratinocytes and fibroblasts, in most cases, the diagnosis is most readily, and least invasively, confirmed via molecular genetic testing.

Diagnosis confirmation

For molecular diagnosis, because the majority of cases are associated with full-length STS gene deletions, either fluorescence in situ hybridization (FISH) using a DNA probe for the STS gene or chromosome microarray analysis, preferably using a high density oligonucleotide-based array, can be utilized. If FISH is utilized, extension of testing to include analysis of the neighboring KAL1 gene should be performed as a partial screen for a contiguous gene deletion (Figure 3).

Microarray analysis provides more specific diagnostic information regarding the presence or absence of neighboring genes. If necessary, full gene sequencing of STS to screen for point mutations and smaller intragenic rearrangements can be performed for non-deletion cases. One recent study reported partial STS gene deletions in 25% of patients.

Because STS is a gene located near the pseudoautosomal region of the X-chromosome, it largely escapes X-inactivation; enzyme levels in normal females are close to twice the levels in normal males. Carrier females therefore show enzyme activity levels roughly equal to that of normal males; only affected males would be truly deficient. Secondary deficiency of STS activity can also occur in multiple sulfatase deficiency (MIM #272200), an autosomal recessive disorder with progressive neurodegeneration and features of a lysosomal storage disease.

Maternal urinary sterol analysis may also be utilized for diagnostic support in non-deletion prenatal cases. In addition, the level of cholesterol sulfate may be measured in the skin, but these assays are less specific for pure STS deficiency.

Who is at Risk for Developing this Disease?

Any male with an STS gene deletion or pathologic point mutation in the STS gene is expected to show features of XLI. Homozygous females, although rare, would also be expected to be affected. Carrier females typically show no features except for those related to pregnancy and the perinatal period although they may have asymptomatic corneal opacities.

It has been proposed that co-existing mutations in filaggrin may modify the severity of the ichthyosis in XLI, but this concept has recently been challenged.

What is the Cause of the Disease?

Etiology

STS is an enzyme that cleaves sulfate groups from sulfated sterols including dehydroepiandrosterone sulfate, cholesterol sulfate, pregnenolone sulfate and androstenediol-3-sulfate to produce sulfate-free steroids that are biologically active. In the placenta, STS deficiency results in failure of cleavage of estriol sulfate and placental estriol deficiency. In the skin, STS is located in the epidermis and regulates local steroid and lipid production. About 10% of epidermal lipids are sterols including cholesterol sulfate. The normal cleavage of cholesterol sulfate by STS results in the normal desquamation of the skin via degradation of corneodesmosomes.

Pathophysiology

In STS deficiency, cholesterol sulfate levels are increased in the stratum corneum, which in turn leads to increased cohesiveness of the cells and a retention type of hyperkeratosis with increased scaling.

Systemic Implications and Complications

Symptoms in most affected males are limited to the skin. Asymptomatic corneal opacities are found in 10% to 50% of affected males and 25% of carrier females using a slit lamp. They are very fine, punctate opacities that are usually deposited in the posterior corneal stroma or Descemet membrane.

About 20% of affected males have cryptorchidism, which must be corrected surgically to prevent malignant degeneration of intra-abdominal testes. However, in addition, and unrelated to any preceding history of cryptorchidism, there is a small risk of testicular germ cell tumors. The latter is not related to a preceding history of cryptorchidism. Nor is the cryptorchidism related to co-deletion of contiguous genes, including the Kallmann syndrome gene locus.

In addition to the corneal opacities and gonadal variations noted above, deletions of contiguous genes along with STS produce a more complex phenotype. The order of genes that may be co-deleted with STS, starting from the telomeric end of the short arm of the X chromosome and proceeding through STS towards the centromere is: SHOX, ARSE, NLGN4, VCX3A, STS, VCX, VCX2, VCX3B, KAL1, and GPR143/OA1 (Figure 3).

The resulting phenotype roughly corresponds to the specific genes that are deleted. Females with large deletions have occasionally been affected, in part dependent on their pattern of X-inactivation in relevant tissues.

The photos in Figure 4 and Figure 5 show a boy with 46,XY karyotype and a contiguous gene deletion extending from the SHOX gene (not shown) through STS (including ARSE, but not including the Kallmann locus). SHOX stands for short stature homeobox gene; SHOX deletions/mutations can be associated with idiopathic short stature or Leri-Weil dyschondrosteosis/Madelung syndrome. ARSE, arylsulfatase E, underlies a form of X-linked chrondrodysplasia punctata. This boy has short stature, cognitive disability, brachydactyly, craniofacial variations and interestingly, only mild cutaneous scaling involving the ears, upper chest, and the front of his neck. His mother, who carries the deletion, has Madelung deformity and short stature.

Figure 4.

A boy with a contiguous gene deletion that includes STS as well as the CDPX and SHOX genes. He has mild scaling on the anterior neck due to the STS deletion.

Figure 5.

A boy with a contiguous gene deletion that includes STS as well as the CDPX and SHOX genes. He has brachydactyly due to deletion of SHOX and CDPX plus mild scaling and accentuated skin markings due to STS deletion.

Deletions of NLGN4 (neuroligin 4) and VCX3A (variably-charged protein X-A, a member of a family of repetitive sequences scattered over this region (see Figure 3) have been variably associated with cognitive deficiency and/or autistic features. Deletion of KAL1 causes X-linked Kallmann syndrome (hypogonadotropic hypogonadism with anosmia). GPR143 is the gene for X-linked (Nettleship-Falls) ocular albinism (OA1).

Individuals found to have larger contiguous gene deletions will clearly need a more multidisciplinary approach to management. Therefore it is important to assess the child for other abnormalities such as short stature, developmental delay or behavioral issues, hypogonadism, renal anomalies, and visual problems.

In a recent series of pregnancies that were ascertained because of low serum unconjugated estriol levels in the mothers, a revised estimate of the population incidence of XLI was 1 in 1513. In cases of sporadic STS deficiency with no family history of XLI, the frequency of a contiguous gene deletion syndrome involving STS was 8.3%.

Other causes of low estriol levels include trisomy 21, trisomy 18, and Smith-Lemli-Opitz syndrome, a recessive disorder of cholesterol biosynthesis due to deficiency of 7-dehydrocholesterol reductase. There has been a recent association of intragenic STS single nucleotide polymorphisms (SNPs) with attention deficit hyperactivity disorder (ADHD). Additional confirmatory studies are in progress.

Treatment Options

Standard approaches to the management of XLI involve facilitating the shedding of scale and inhibiting excessive keratinization. Oral therapy, eg, with retinoids, is rarely necessary in XLI. Combinations of moisturizing agents and keratolytics are typically employed and humidification of the ambient air may be helpful.

For severe exacerbations, nightly application of topical 40% to 60% propylene glycol in water to the body with occlusion has been suggested. The process can be repeated nightly until excess scales are eliminated, then used more periodically along with other “maintenance” therapy. Long soaking baths with mechanical debridement using a rough sponge can also be helpful. Bath oils that lubricate, followed by topical emollients, may also be helpful.

In older children and adults, useful topical keratolytics are lactic acid, glycolic acid, salicylic acid (0.5% to 60%), and urea (5% to 10%). Propylene glycol 40% to 60% in water as well as a 10% cholesterol cream have been used with success, sometimes in combination with an alpha-hydroxy acid. In infants, however, these agents may be associated with high levels of cutaneous absorption and subsequent toxicity. Therefore, moisturizing agents are the favored treatment modality in this age group.

Topical retinoic acid derivatives (eg, isotretinoin and tazarotene) have also been utilized in the treatment of XLI.

Affected males and their physicians should also be told of the small risk of testicular tumors and encouraged to perform periodic testicular examination. Males with contiguous gene deletions (eg, Figure 4 and Figure 5) have other clinical features that may need directed treatment. Clinical genetics evaluation and counseling should be offered in simplex cases and is imperative in cases with contiguous gene deletions and a complex phenotype.

Optimal Therapeutic Approach for this Disease

Topical treatments are first-line and mostly sufficient for management. Examples:

--Emollients: includes glycerol, vitamin E acetate. This would be the mainstay of treatment for infants and young children.

--Topical retinoids: 0.025% to 0.05% tretinoin once daily, or 0.1% tazarotene once daily

--Systemic treatment: should not be necessary, but potentially, oral retinoids can be used in severe, adult cases.

Patient Management

From a cutaneous standpoint, the patient is usually easily managed with conservative treatment, preferably using only emollients with occasional keratolytics for maintenance. Ongoing ophthalmologic follow-up should not be necessary.

Periodic testicular examination is also suggested, with any detected variation in shape or size of the testes meriting more directed evaluation by imaging studies, tumor markers, and surgical consultation.

Systemic manifestations of contiguous gene deletions may require management by multiple medical and surgical specialists, for example, in genetics, endocrinology, orthopedics, ophthalmology, and other fields.

Prenatal testing is certainly possible and is easily justified if there is a contiguous gene deletion syndrome with more serious consequences. It can also be useful for reassurance if maternal serum screening detects low estriol levels. Parents might really want the reassurance obtainable via prenatal testing that XLI is all that they’re dealing with. Also, there may be modest differences in the way labor and delivery are handled.

Unusual Clinical Scenarios to Consider in Patient Management

A pregnancy of a male fetus with XLI can be associated with very low maternal serum estriol levels. This typically provokes a high level of anxiety because of the possibility of more serious chromosomal and genetic conditions (eg, Down syndrome, Smith-Lemli-Opitz syndrome, multiple sulfatase deficiency). Such a situation merits immediate evaluation and diagnostic testing for confirmation of the diagnosis.

The patient with a contiguous gene deletion will require a multidisciplinary approach to management as discussed above.

(The authors reported that both daily application of topical tazarotene and weekly application of glycolic acid resulted in marked improvement of the scaling in XLI, but that the topical tazarotene effects lasted longer.)

(This large study aimed to ascertain all prenatally diagnosed cases of STS deficiency over a 5-year period, revised the population incidence of the disorder based on this data, and determined the incidence of larger contiguous STS gene deletions in the study population.)

(Among 40 subjects with XLI, the authors detected complete gene deletions in 30 and partial deletions in 10, a higher rate of partial deletions than in previous reports. There was no genotype-phenotype correlation. )

(Two brothers with an STS point mutation and differing degrees of severity were reported. The more severely affected brother also had a nonsense, presumably pathologic, mutation in filaggrin. Thus, the authors proposed that filaggrin mutations may be modifiers of the cutaneous phenotype in XLI.)

(Two brothers with differing clinical severity of ichthyosis due to STS deficiency are presented. Both were deleted for the STS gene and both had the same single-base deletion/frameshift mutation in the filaggrin gene. The authors noted that because of the brothers’ concordant STS and FLG genotypes, there must be other genetic modifiers of XLI beyond FLG.)

(A three-generation family with a contiguous gene deletion involving VCX-A and NLGN4, STS, and KAL1 was studied. Two affected adult males were discordant with respect to their intelligence (one normal, one impaired), suggesting that there may be other genetic and environmental modifiers of this aspect of the phenotype.)

[Epub ahead of print].(The authors studied STS SNPs in a series of males with ADHD and the expression of STS in the brain. They did not replicate one previously noted SNP association (rs12861247) with ADHD, but a different SNP, rs17268988, was significantly associated with inattentive symptoms. High STS expression was noted in the developing cerebellar neuroepithelium, basal ganglia, thalamus, pituitary gland, hypothalamus and choroid plexus, and the authors suggested that genetic variants affecting STS expression and/or activity might indeed influence brain function in regions linked to ADHD.)

(This was a large genetic association study of 450 boys with ADHD and their parents using 12 SNPs in STS and haplotype analysis. The authors noted overtransmission of the rs12861247 SNP to boys with ADHD, a marker previously associated with ADHD risk. They correlated this particular SNP with decreased STS gene expression in normal frontal cortex post-mortem brain, noted that the brain and adipose tissue STS transcripts are unique compared with STS transcripts in other tissues.)